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Abstract

Childhood undernutrition is a major global health burden that is only partially resolved by nutritional interventions. Both chronic and acute forms of child undernutrition are characterized by derangements in multiple biological systems including metabolism, immunity, and endocrine systems. A growing body of evidence supports a role of the gut microbiome in mediating these pathways influencing early life growth. Observational studies report alterations in the gut microbiome of undernourished children, while preclinical studies suggest that this can trigger intestinal enteropathy, alter host metabolism, and disrupt immune-mediated resistance against enteropathogens, each of which contribute to poor early life growth. Here, we compile evidence from preclinical and clinical studies and describe the emerging pathophysiological pathways by which the early life gut microbiome influences host metabolism, immunity, intestinal function, endocrine regulation, and other pathways contributing to child undernutrition. We discuss emerging microbiome-directed therapies and consider future research directions to identify and target microbiome-sensitive pathways in child undernutrition.

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2023-08-21
2024-04-21
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Literature Cited

  1. 1.
    Acosta A, De Burga R, Chavez C, Flores J, Olortegui M et al. 2017. Relationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: findings from the MAL-ED birth cohort study. BMJ Glob. Health 2:4e000370
    [Google Scholar]
  2. 2.
    Alves da Silva AV, de Castro Oliveira SB, Di Rienzi SC, Brown-Steinke K, Dehan LM et al. 2019. Murine methyl donor deficiency impairs early growth in association with dysmorphic small intestinal crypts and reduced gut microbial community diversity. Curr. Dev. Nutr. 3:1nzy070
    [Google Scholar]
  3. 3.
    Amadi B, Fagbemi AO, Kelly P, Mwiya M, Torrente F et al. 2009. Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus. Am. J. Clin. Nutr. 89:2592–600
    [Google Scholar]
  4. 4.
    Amadi B, Zyambo K, Chandwe K, Besa E, Mulenga C et al. 2021. Adaptation of the small intestine to microbial enteropathogens in Zambian children with stunting. Nat. Microbiol. 6:4445–54
    [Google Scholar]
  5. 5.
    Ansaldo E, Farley TK, Belkaid Y. 2021. Control of immunity by the microbiota. Annu. Rev. Immunol. 39:449–79
    [Google Scholar]
  6. 6.
    Attia S, Versloot CJ, Voskuijl W, van Vliet SJ, Di Giovanni V et al. 2016. Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study. Am. J. Clin. Nutr. 104:1441–49
    [Google Scholar]
  7. 7.
    Barratt MJ, Nuzhat S, Ahsan K, Frese SA, Arzamasov AA et al. 2022. Bifidobacterium infantis treatment promotes weight gain in Bangladeshi infants with severe acute malnutrition. Sci. Transl. Med. 14:640eabk1107
    [Google Scholar]
  8. 8.
    Bartelt LA, Bolick DT, Mayneris-Perxachs J, Kolling GL, Medlock GL et al. 2017. Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli. PLOS Pathog. 13:7e1006471
    [Google Scholar]
  9. 9.
    Bartz S, Mody A, Hornik C, Bain J, Muehlbauer M et al. 2014. Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality. J. Clin. Endocrinol. Metab. 99:62128–37
    [Google Scholar]
  10. 10.
    Bhattacharjee A, Burr AHP, Overacre-Delgoffe AE, Tometich JT, Yang D et al. 2021. Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy. Immunity 54:81745–57.e7
    [Google Scholar]
  11. 11.
    Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P et al. 2013. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 382:9890427–51
    [Google Scholar]
  12. 12.
    Bourdon C, Lelijveld N, Thompson D, Dalvi PS, Gonzales GB et al. 2019. Metabolomics in plasma of Malawian children 7 years after surviving severe acute malnutrition: “ChroSAM” a cohort study. EBioMedicine 45:464–72
    [Google Scholar]
  13. 13.
    Bourke CD, Berkley JA, Prendergast AJ. 2016. Immune dysfunction as a cause and consequence of malnutrition. Trends Immunol. 37:386–98
    [Google Scholar]
  14. 14.
    Bourke CD, Jones KDJ, Prendergast AJ. 2019. Current understanding of innate immune cell dysfunction in childhood undernutrition. Front. Immunol. 10:1728
    [Google Scholar]
  15. 15.
    Brown EM, Wlodarska M, Willing BP, Vonaesch P, Han J et al. 2015. Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model. Nat. Commun. 6:7806
    [Google Scholar]
  16. 16.
    Burgess SL, Leslie JL, Uddin J, Oakland DN, Gilchrist C et al. 2020. Gut microbiome communication with bone marrow regulates susceptibility to amebiasis. J. Clin. Investig. 130:84019–24
    [Google Scholar]
  17. 17.
    Bwakura-Dangarembizi M, Dumbura C, Amadi B, Ngosa D, Majo FD et al. 2021. Risk factors for postdischarge mortality following hospitalization for severe acute malnutrition in Zimbabwe and Zambia. Am. J. Clin. Nutr. 113:3665–74
    [Google Scholar]
  18. 18.
    Calder N, Walsh K, Olupot-Olupot P, Ssenyondo T, Muhindo R et al. 2021. Modifying gut integrity and microbiome in children with severe acute malnutrition using legume-based feeds (MIMBLE): a pilot trial. Cell Rep. Med. 2:5100280
    [Google Scholar]
  19. 19.
    Campbell JM, Fahey GC, Wolf BW. 1997. Selected indigestible oligosaccharides affect large bowel mass, cecal and fecal short-chain fatty acids, pH and microflora in rats. J. Nutr. 127:1130–36
    [Google Scholar]
  20. 20.
    Candido EP, Reeves R, Davie JR. 1978. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14:1105–13
    [Google Scholar]
  21. 21.
    Castro-Mejía JL, O'Ferrall S, Krych Ł, O'Mahony E, Namusoke H et al. 2020. Restitution of gut microbiota in Ugandan children administered with probiotics (Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12) during treatment for severe acute malnutrition. Gut Microbes 11:4855–67
    [Google Scholar]
  22. 22.
    Chang HW, McNulty NP, Hibberd MC, O'Donnell D, Cheng J et al. 2021. Gut microbiome contributions to altered metabolism in a pig model of undernutrition. PNAS 118:21e2024446118
    [Google Scholar]
  23. 23.
    Charbonneau MR, O'Donnell D, Blanton LV, Totten SM, Davis JC et al. 2016. Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell 164:5859–71
    [Google Scholar]
  24. 24.
    Checkley W, Buckley G, Gilman RH, Assis AM, Guerrant RL et al. 2008. Multi-country analysis of the effects of diarrhoea on childhood stunting. Int. J. Epidemiol. 37:4816–30
    [Google Scholar]
  25. 25.
    Chen RY, Kung VL, Das S, Hossain MS, Hibberd MC et al. 2020. Duodenal microbiota in stunted undernourished children with enteropathy. N. Engl. J. Med. 383:4321–33
    [Google Scholar]
  26. 26.
    Chen RY, Mostafa I, Hibberd MC, Das S, Mahfuz M et al. 2021. A microbiota-directed food intervention for undernourished children. N. Engl. J. Med. 384:161517–28
    [Google Scholar]
  27. 27.
    Chisti MJ, Tebruegge M, La Vincente S, Graham SM, Duke T 2009. Pneumonia in severely malnourished children in developing countries—mortality risk, aetiology and validity of WHO clinical signs: a systematic review. Trop. Med. Int. Health 14:101173–89
    [Google Scholar]
  28. 28.
    Christian P, Lee SE, Donahue Angel M, Adair LS, Arifeen SE et al. 2013. Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries. Int. J. Epidemiol. 42:51340–55
    [Google Scholar]
  29. 29.
    Cowardin CA, Ahern PP, Kung VL, Hibberd MC, Cheng J et al. 2019. Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition. PNAS 116:2411988–96
    [Google Scholar]
  30. 30.
    Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. 1987. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28:101221–27
    [Google Scholar]
  31. 31.
    Daalderop LA, Wieland BV, Tomsin K, Reyes L, Kramer BW et al. 2018. Periodontal disease and pregnancy outcomes: overview of systematic reviews. JDR Clin. Trans. Res. 3:110–27
    [Google Scholar]
  32. 32.
    Dasanayake AP, Li Y, Wiener H, Ruby JD, Lee MJ. 2005. Salivary Actinomyces naeslundii genospecies 2 and Lactobacillus casei levels predict pregnancy outcomes. J. Periodontol. 76:2171–77
    [Google Scholar]
  33. 33.
    De Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P et al. 1997. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J. Clin. Investig. 99:4643–50
    [Google Scholar]
  34. 34.
    Derbyshire E, Obeid R. 2020. Choline, neurological development and brain function: a systematic review focusing on the first 1000 days. Nutrients 12:61731
    [Google Scholar]
  35. 35.
    Desai C, Handley SA, Rodgers R, Rodriguez C, Ordiz MI et al. 2020. Growth velocity in children with Environmental Enteric Dysfunction is associated with specific bacterial and viral taxa of the gastrointestinal tract in Malawian children. PLOS Negl. Trop. Dis. 14:6e0008387
    [Google Scholar]
  36. 36.
    Dewey KG, Stewart CP, Wessells KR, Prado EL, Arnold CD. 2021. Small-quantity lipid-based nutrient supplements for the prevention of child malnutrition and promotion of healthy development: overview of individual participant data meta-analysis and programmatic implications. Am. J. Clin. Nutr. 114:Suppl. 13S–14S
    [Google Scholar]
  37. 37.
    Dewey KG, Arnold CD, Wessells KR, Prado EL, Abbeddou S et al. 2022. Preventive small-quantity lipid-based nutrient supplements reduce severe wasting and severe stunting among young children: an individual participant data meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 116:1314–33
    [Google Scholar]
  38. 38.
    Di Giovanni V, Bourdon C, Wang DX, Seshadri S, Senga E et al. 2016. Metabolomic changes in serum of children with different clinical diagnoses of malnutrition. J. Nutr. 146:2436–44
    [Google Scholar]
  39. 39.
    Di Luccia B, Ahern PP, Griffin NW, Cheng J, Guruge JL et al. 2020. Combined prebiotic and microbial intervention improves oral cholera vaccination responses in a mouse model of childhood undernutrition. Cell Host Microbe 27:6899–908.e5
    [Google Scholar]
  40. 40.
    DiGiulio DB, Callahan BJ, McMurdie PJ, Costello EK, Lyell DJ et al. 2015. Temporal and spatial variation of the human microbiota during pregnancy. PNAS 112:3511060–65
    [Google Scholar]
  41. 41.
    Dinh DM, Ramadass B, Kattula D, Sarkar R, Braunstein P et al. 2016. Longitudinal analysis of the intestinal microbiota in persistently stunted young children in South India. PLOS ONE 11:5e0155405
    [Google Scholar]
  42. 42.
    Donowitz JR, Haque R, Kirkpatrick BD, Alam M, Lu M et al. 2016. Small intestine bacterial overgrowth and environmental enteropathy in Bangladeshi children. mBio 7:1e02102–15
    [Google Scholar]
  43. 43.
    Doyle R, Gondwe A, Fan YM, Maleta K, Ashorn P et al. 2018. A Lactobacillus-deficient vaginal microbiota dominates postpartum women in rural Malawi. Appl. Environ. Microbiol. 84:6e02150–17
    [Google Scholar]
  44. 44.
    Ducarmon QR, Zwittink RD, Hornung BVH, van Schaik W, Young VB, Kuijper EJ. 2019. Gut microbiota and colonization resistance against bacterial enteric infection. Microbiol. Mol. Biol. Rev. 83:3e00007–19
    [Google Scholar]
  45. 45.
    Evans C, Chasekwa B, Rukobo S, Govha M, Mutasa K et al. 2020. Inflammation, cytomegalovirus and the growth hormone axis in HIV-exposed uninfected Zimbabwean infants. Aids 34:142045–50
    [Google Scholar]
  46. 46.
    Famouri F, Khoshdel A, Golshani A, Kheiri S, Saneian H, Kelishadi R. 2014. Effects of synbiotics on treatment of children with failure to thrive: a triple blind placebo-controlled trial. J. Res. Med. Sci. 19:111046–50
    [Google Scholar]
  47. 47.
    Ferretti P, Pasolli E, Tett A, Asnicar F, Gorfer V et al. 2018. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe 24:1133–45.e5
    [Google Scholar]
  48. 48.
    Fettweis JM, Serrano MG, Brooks JP, Edwards DJ, Girerd PH et al. 2019. The vaginal microbiome and preterm birth. Nat. Med. 25:61012–21
    [Google Scholar]
  49. 49.
    Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Kung VL et al. 2019. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Science 365:6449eaau4732
    [Google Scholar]
  50. 50.
    Giallourou N, Fardus-Reid F, Panic G, Veselkov K, McCormick BJJ et al. 2020. Metabolic maturation in the first 2 years of life in resource-constrained settings and its association with postnatal growths. Sci. Adv. 6:15eaay5969
    [Google Scholar]
  51. 51.
    Gough EK, Stephens DA, Moodie EE, Prendergast AJ, Stoltzfus RJ et al. 2015. Linear growth faltering in infants is associated with Acidaminococcus sp. and community-level changes in the gut microbiota. Microbiome 3:24
    [Google Scholar]
  52. 52.
    Gough EK, Moulton LH, Mutasa K, Ntozini R, Stoltzfus RJ et al. 2020. Effects of improved water, sanitation, and hygiene and improved complementary feeding on environmental enteric dysfunction in children in rural Zimbabwe: a cluster-randomized controlled trial. PLOS Negl. Trop. Dis. 14:2e0007963
    [Google Scholar]
  53. 53.
    Grenov B, Namusoke H, Lanyero B, Nabukeera-Barungi N, Ritz C et al. 2017. Effect of probiotics on diarrhea in children with severe acute malnutrition: a randomized controlled study in Uganda. J. Pediatr. Gastroenterol. Nutr. 64:3396–403
    [Google Scholar]
  54. 54.
    Grover M, Kashyap PC. 2014. Germ-free mice as a model to study effect of gut microbiota on host physiology. Neurogastroenterol. Motil. 26:6745–48
    [Google Scholar]
  55. 55.
    Guerrant RL, Leite AM, Pinkerton R, Medeiros PH, Cavalcante PA et al. 2016. Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in northeast Brazil. PLOS ONE 11:9e0158772
    [Google Scholar]
  56. 56.
    Haberman Y, Iqbal NT, Ghandikota S, Mallawaarachchi I, Tzipi Braun et al. 2021. Mucosal genomics implicate lymphocyte activation and lipid metabolism in refractory environmental enteric dysfunction. Gastroenterology 160:62055–71.e0
    [Google Scholar]
  57. 57.
    Han H, Yi B, Zhong R, Wang M, Zhang S et al. 2021. From gut microbiota to host appetite: gut microbiota-derived metabolites as key regulators. Microbiome 9:1162
    [Google Scholar]
  58. 58.
    Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H et al. 2012. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487:7408477–81
    [Google Scholar]
  59. 59.
    Hossain M, Nahar B, Haque MA, Mondal D, Mahfuz M et al. 2019. Serum adipokines, growth factors, and cytokines are independently associated with stunting in Bangladeshi children. Nutrients 11:81827
    [Google Scholar]
  60. 60.
    Huus K, Bauer K, Brown E, Bozorgmehr T, Woodward S et al. 2020. Commensal bacteria modulate immunoglobulin A binding in response to host nutrition. Cell Host Microbe 27:909–21.e5
    [Google Scholar]
  61. 61.
    Huus KE, Rodriguez-Pozo A, Kapel N, Nestoret A, Habib A et al. 2020. Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study. Microbiome 8:1113
    [Google Scholar]
  62. 62.
    Huus KE, Hoang TT, Creus-Cuadros A, Cirstea M, Vogt SL et al. 2021. Cross-feeding between intestinal pathobionts promotes their overgrowth during undernutrition. Nat. Commun. 12:16860
    [Google Scholar]
  63. 63.
    Huus KE, Petersen C, Finlay BB. 2021. Diversity and dynamism of IgA-microbiota interactions. Nat. Rev. Immunol. 21:514–25
    [Google Scholar]
  64. 64.
    Iqbal MS, Rahman S, Haque MA, Bhuyan MJ, Faruque ASG, Ahmed T. 2019. Lower intakes of protein, carbohydrate, and energy are associated with increased global DNA methylation in 2- to 3-year-old urban slum children in Bangladesh. Matern. Child Nutr. 15:3e12815
    [Google Scholar]
  65. 65.
    Jones KDJ, Hünten-Kirsch B, Laving AMR, Munyi CW, Ngari M et al. 2014. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med. 12:1133
    [Google Scholar]
  66. 66.
    Jonker H, Capelle N, Lanes A, Wen SW, Walker M, Corsi DJ. 2020. Maternal folic acid supplementation and infant birthweight in low- and middle-income countries: a systematic review. Matern. Child Nutr. 16:1e12895
    [Google Scholar]
  67. 67.
    Kamil RZ, Murdiati A, Juffrie M, Nakayama J, Rahayu ES. 2021. Gut microbiota and short-chain fatty acid profile between normal and moderate malnutrition children in Yogyakarta, Indonesia. Microorganisms 9:1127
    [Google Scholar]
  68. 68.
    Kamng'ona AW, Young R, Arnold CD, Patson N, Jorgensen JM et al. 2020. Provision of lipid-based nutrient supplements to mothers during pregnancy and 6 months postpartum and to their infants from 6 to 18 months promotes infant gut microbiota diversity at 18 months of age but not microbiota maturation in a rural Malawian setting: secondary outcomes of a randomized trial. J. Nutr. 150:4918–28
    [Google Scholar]
  69. 69.
    Kara SS, Volkan B, Erten I. 2019. Lactobacillus rhamnosus GG can protect malnourished children. Benef. Microbes 10:3237–44
    [Google Scholar]
  70. 70.
    Kau AL, Planer JD, Liu J, Rao S, Yatsunenko T et al. 2015. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Sci. Transl. Med. 7:276276ra24
    [Google Scholar]
  71. 71.
    Kennedy EA, King KY, Baldridge MT. 2018. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front. Physiol. 9:1534
    [Google Scholar]
  72. 72.
    Kerac M, Bunn J, Seal A, Thindwa M, Tomkins A et al. 2009. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi. Lancet 374:9684136–44
    [Google Scholar]
  73. 73.
    Kerac M, Bunn J, Chagaluka G, Bahwere P, Tomkins A et al. 2014. Follow-up of post-discharge growth and mortality after treatment for severe acute malnutrition (FuSAM study): a prospective cohort study. PLOS ONE 9:6e96030
    [Google Scholar]
  74. 74.
    Khan Mirzaei M, Khan MAA, Ghosh P, Taranu ZE, Taguer M et al. 2020. Bacteriophages isolated from stunted children can regulate gut bacterial communities in an age-specific manner. Cell Host Microbe 27:2199–212.e5
    [Google Scholar]
  75. 75.
    King BJ, Keegan AR, Phillips R, Fanok S, Monis PT. 2012. Dissection of the hierarchy and synergism of the bile derived signal on Cryptosporidium parvum excystation and infectivity. Parasitology 139:121533–46
    [Google Scholar]
  76. 76.
    Kortekangas E, Fan YM, Chaima D, Lehto KM, Malamba-Banda C et al. 2022. Associations between gut microbiota and intestinal inflammation, permeability and damage in young Malawian children. J. Trop. Pediatr. 68:2fmac012
    [Google Scholar]
  77. 77.
    Kosek MN, Mduma E, Kosek PS, Lee GO, Svensen E et al. 2016. Plasma tryptophan and the kynurenine-tryptophan ratio are associated with the acquisition of statural growth deficits and oral vaccine underperformance in populations with environmental enteropathy. Am. J. Trop. Med. Hyg. 95:4928–37
    [Google Scholar]
  78. 78.
    Kosek MN, Ahmed T, Bhutta Z, Caulfield L, Guerrant R et al. 2017. Causal pathways from enteropathogens to environmental enteropathy: findings from the MAL-ED birth cohort study. EBioMedicine 18:109–17
    [Google Scholar]
  79. 79.
    Kristensen KH, Wiese M, Rytter MJ, Özçam M, Hansen LH et al. 2016. Gut microbiota in children hospitalized with oedematous and non-oedematous severe acute malnutrition in Uganda. PLOS Negl. Trop. Dis. 10:1e0004369
    [Google Scholar]
  80. 80.
    Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL. 2002. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107:4452–60
    [Google Scholar]
  81. 81.
    Lelijveld N, Seal A, Wells JC, Kirkby J, Opondo C et al. 2016. Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study. Lancet Glob. Health 4:9e654–62
    [Google Scholar]
  82. 82.
    Lelijveld N, Jalloh AA, Kampondeni SD, Seal A, Wells JC et al. 2019. Brain MRI and cognitive function seven years after surviving an episode of severe acute malnutrition in a cohort of Malawian children. Public Health Nutr. 22:81406–14
    [Google Scholar]
  83. 83.
    Maleta K, Fan Y, Luoma J, Ashorn U, Bendabenda J et al. 2020. Infections and systemic inflammation are associated with lower plasma concentration of insulin-like growth factor I among Malawian children. Am. J. Clin. Nutr. 113:380–90
    [Google Scholar]
  84. 84.
    Mayneris-Perxachs J, Bolick DT, Leng J, Medlock GL, Kolling GL et al. 2016. Protein- and zinc-deficient diets modulate the murine microbiome and metabolic phenotype. Am. J. Clin. Nutr. 104:51253–62
    [Google Scholar]
  85. 85.
    Mayneris-Perxachs J, Lima AA, Guerrant RL, Leite ÁM, Moura AF et al. 2016. Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children. Sci. Rep. 6:19780
    [Google Scholar]
  86. 86.
    Mayneris-Perxachs J, Swann JR. 2018. Metabolic phenotyping of malnutrition during the first 1000 days of life. Eur. J. Nutr. 58:909–30
    [Google Scholar]
  87. 87.
    Moretti A, Paoletta M, Liguori S, Bertone M, Toro G, Iolascon G. 2020. Choline: an essential nutrient for skeletal muscle. Nutrients 12:72144
    [Google Scholar]
  88. 88.
    Mwene-Batu P, Bisimwa G, Baguma M, Chabwine J, Bapolisi A et al. 2020. Long-term effects of severe acute malnutrition during childhood on adult cognitive, academic and behavioural development in African fragile countries: the Lwiro cohort study in Democratic Republic of the Congo. PLOS ONE 15:12e0244486
    [Google Scholar]
  89. 89.
    Nabwera HM, Espinoza JL, Worwui A, Betts M, Okoi C et al. 2021. Interactions between fecal gut microbiome, enteric pathogens, and energy regulating hormones among acutely malnourished rural Gambian children. EBioMedicine 73:103644
    [Google Scholar]
  90. 90.
    Njunge J, Gonzales GB, Ngari M, Thitiri J, Bandsma R, Berkley J. 2021. Systemic inflammation is negatively associated with early post discharge growth following acute illness among severely malnourished children—a pilot study. Wellcome Open Res. 5:248
    [Google Scholar]
  91. 91.
    Njunge JM, Gwela A, Kibinge NK, Ngari M, Nyamako L et al. 2019. Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition. Sci. Rep. 9:15981
    [Google Scholar]
  92. 92.
    Ordiz MI, Stephenson K, Agapova S, Wylie KM, Maleta K et al. 2017. Environmental enteric dysfunction and the fecal microbiota in Malawian children. Am. J. Trop. Med. Hyg. 96:2473–76
    [Google Scholar]
  93. 93.
    Ordiz MI, Janssen S, Humphrey G, Ackermann G, Stephenson K et al. 2020. The effect of legume supplementation on the gut microbiota in rural Malawian infants aged 6 to 12 months. Am. J. Clin. Nutr. 111:4884–92
    [Google Scholar]
  94. 94.
    Pan WH, Sommer F, Falk-Paulsen M, Ulas T, Best P et al. 2018. Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development. Genome Med. 10:127
    [Google Scholar]
  95. 95.
    Parker EP, Ramani S, Lopman BA, Church JA, Iturriza-Gómara M et al. 2018. Causes of impaired oral vaccine efficacy in developing countries. Future Microbiol. 13:197–118
    [Google Scholar]
  96. 96.
    Pasolli E, Asnicar F, Manara S, Zolfo M, Karcher N et al. 2019. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell 176:3649–62.e20
    [Google Scholar]
  97. 97.
    Passmore IJ, Letertre MPM, Preston MD, Bianconi I, Harrison MA et al. 2018. Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria. PLOS Pathog. 14:9e1007191
    [Google Scholar]
  98. 98.
    Patterson GT, Osorio EY, Peniche A, Dann SM, Cordova E et al. 2022. Pathologic inflammation in malnutrition is driven by proinflammatory intestinal microbiota, large intestine barrier dysfunction, and translocation of bacterial lipopolysaccharide. Front. Immunol. 13:846155
    [Google Scholar]
  99. 99.
    Peng L, Li ZR, Green RS, Holzman IR, Lin J. 2009. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J. Nutr. 139:91619–25
    [Google Scholar]
  100. 100.
    Peter CJ, Fischer LK, Kundakovic M, Garg P, Jakovcevski M et al. 2016. DNA methylation signatures of early childhood malnutrition associated with impairments in attention and cognition. Biol. Psychiatry 80:10765–74
    [Google Scholar]
  101. 101.
    Poinsot P, Schwarzer M, Peretti N, Leulier F. 2018. The emerging connections between IGF1, the intestinal microbiome, Lactobacillus strains and bone growth. J. Mol. Endocrinol. 61:1T103–13
    [Google Scholar]
  102. 102.
    Prendergast A, Kelly P. 2012. Enteropathies in the developing world: neglected effects on global health. Am. J. Trop. Med. Hyg. 86:5756–63
    [Google Scholar]
  103. 103.
    Prendergast AJ, Humphrey JH. 2014. The stunting syndrome in developing countries. Paediatr. Int. Child Health 34:4250–65
    [Google Scholar]
  104. 104.
    Prendergast AJ, Rukobo S, Chasekwa B, Mutasa K, Ntozini R et al. 2014. Stunting is characterized by chronic inflammation in Zimbabwean infants. PLOS ONE 9:2e86928
    [Google Scholar]
  105. 105.
    Prendergast AJ, Kelly P. 2016. Interactions between intestinal pathogens, enteropathy and malnutrition in developing countries. Curr. Opin. Infect. Dis. 29:3229–36
    [Google Scholar]
  106. 106.
    Queipo-Ortuño MI, Seoane LM, Murri M, Pardo M, Gomez-Zumaquero JM et al. 2013. Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels. PLOS ONE 8:5e65465
    [Google Scholar]
  107. 107.
    Raman AS, Gehrig JL, Venkatesh S, Chang HW, Hibberd MC et al. 2019. A sparse covarying unit that describes healthy and impaired human gut microbiota development. Science 365:6449eaau4735
    [Google Scholar]
  108. 108.
    Reyes A, Blanton LV, Cao S, Zhao G, Manary M et al. 2015. Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. PNAS 112:3811941–46
    [Google Scholar]
  109. 109.
    Robertson RC, Manges AR, Finlay BB, Prendergast AJ. 2018. The human microbiome and child growth; first 1000 days and beyond. Trends Microbiol. 27:131–47
    [Google Scholar]
  110. 110.
    Robertson RC, Edens TJ, Carr L, Mutasa K, Gough EK et al. 2023. The gut microbiome and early-life growth in a population with high prevalence of stunting. Nat. Commun. 14:1654
    [Google Scholar]
  111. 111.
    Rogawski ET, Liu J, Platts-Mills JA, Kabir F, Lertsethtakarn P et al. 2018. Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study. Lancet Glob. Health 6:12e1319–28
    [Google Scholar]
  112. 112.
    Rogawski McQuade ET, Platts-Mills JA, Gratz J, Zhang J, Moulton LH et al. 2020. Impact of water quality, sanitation, handwashing, and nutritional interventions on enteric infections in rural Zimbabwe: the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial. J. Infect. Dis. 221:81379–86
    [Google Scholar]
  113. 113.
    Rouhani S, Griffin NW, Yori PP, Gehrig JL, Olortegui MP et al. 2020. Diarrhea as a potential cause and consequence of reduced gut microbial diversity among undernourished children in Peru. Clin. Infect. Dis. 71:4989–99
    [Google Scholar]
  114. 114.
    Rouhani S, Griffin NW, Yori PP, Olortegui MP, Siguas Salas M et al. 2020. Gut microbiota features associated with Campylobacter burden and postnatal linear growth deficits in a Peruvian birth cohort. Clin. Infect. Dis. 71:41000–7
    [Google Scholar]
  115. 115.
    Rytter MJ, Kolte L, Briend A, Friis H, Christensen VB. 2014. The immune system in children with malnutrition—a systematic review. PLOS ONE 9:8e105017
    [Google Scholar]
  116. 116.
    Salameh E, Morel FB, Zeilani M, Déchelotte P, Marion-Letellier R. 2019. Animal models of undernutrition and enteropathy as tools for assessment of nutritional intervention. Nutrients 11:92233
    [Google Scholar]
  117. 117.
    Schieber AM, Lee YM, Chang MW, Leblanc M, Collins B et al. 2015. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science 350:6260558–63
    [Google Scholar]
  118. 118.
    Schulze KV, Swaminathan S, Howell S, Jajoo A, Lie NC et al. 2019. Edematous severe acute malnutrition is characterized by hypomethylation of DNA. Nat. Commun. 10:15791
    [Google Scholar]
  119. 119.
    Schwarzer M, Gautam UK, Makki K, Lambert A, Brabec T et al. 2023. Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice. Science 379:6634826–33
    [Google Scholar]
  120. 120.
    Schwarzer M, Makki K, Storelli G, Machuca-Gayet I, Srutkova D et al. 2016. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science 351:6275854–57
    [Google Scholar]
  121. 121.
    Semba RD, Zhang P, Gonzalez-Freire M, Moaddel R, Trehan I et al. 2016. The association of serum choline with linear growth failure in young children from rural Malawi. Am. J. Clin. Nutr. 104:1191–97
    [Google Scholar]
  122. 122.
    Semba RD, Gonzalez-Freire M, Moaddel R, Trehan I, Maleta KM et al. 2017. Environmental enteric dysfunction is associated with altered bile acid metabolism. J. Pediatr. Gastroenterol. Nutr. 64:4536–40
    [Google Scholar]
  123. 123.
    Sheppard A, Ngo S, Li X, Boyne M, Thompson D et al. 2017. Molecular evidence for differential long-term outcomes of early life severe acute malnutrition. EBioMedicine 18:274–80
    [Google Scholar]
  124. 124.
    Shivakumar N, Sivadas A, Devi S, Jahoor F, McLaughlin J et al. 2021. Gut microbiota profiles of young South Indian children: child sex-specific relations with growth. PLOS ONE 16:5e0251803
    [Google Scholar]
  125. 125.
    Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R et al. 2013. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339:6119548–54
    [Google Scholar]
  126. 126.
    Stephenson KB, Agapova SE, Divala O, Kaimila Y, Maleta KM et al. 2017. Complementary feeding with cowpea reduces growth faltering in rural Malawian infants: a blind, randomized controlled clinical trial. Am. J. Clin. Nutr. 106:61500–7
    [Google Scholar]
  127. 127.
    Stewart CJ, Ajami NJ, O'Brien JL, Hutchinson DS, Smith DP et al. 2018. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 562:7728583–88
    [Google Scholar]
  128. 128.
    Strand TA, Ulak M, Kvestad I, Henjum S, Ulvik A et al. 2018. Maternal and infant vitamin B12 status during infancy predict linear growth at 5 years. Pediatr. Res. 84:5611–18
    [Google Scholar]
  129. 129.
    Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M et al. 2014. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510:7505417–21
    [Google Scholar]
  130. 130.
    Surono IS, Widiyanti D, Kusumo PD, Venema K. 2021. Gut microbiota profile of Indonesian stunted children and children with normal nutritional status. PLOS ONE 16:1e0245399
    [Google Scholar]
  131. 131.
    Syed S, Manji KP, McDonald CM, Kisenge R, Aboud S et al. 2018. Biomarkers of systemic inflammation and growth in early infancy are associated with stunting in young Tanzanian children. Nutrients 10:91158
    [Google Scholar]
  132. 132.
    Uchiyama R, Kupkova K, Shetty SJ, Linford AS, Pray-Grant MG et al. 2018. Histone H3 lysine 4 methylation signature associated with human undernutrition. PNAS 115:48E11264–73
    [Google Scholar]
  133. 133.
    Vaivada T, Akseer N, Akseer S, Somaskandan A, Stefopulos M, Bhutta ZA. 2020. Stunting in childhood: an overview of global burden, trends, determinants, and drivers of decline. Am. J. Clin. Nutr. 112:Suppl. 2777S–91S
    [Google Scholar]
  134. 134.
    Vatanen T, Ang QY, Siegwald L, Sarker SA, Le Roy CI et al. 2022. A distinct clade of Bifidobacterium longum in the gut of Bangladeshi children thrives during weaning. Cell 185:234280–97.e12
    [Google Scholar]
  135. 135.
    Vonaesch P, Morien E, Andrianonimiadana L, Sanke H, Mbecko JR et al. 2018. Stunted childhood growth is associated with decompartmentalization of the gastrointestinal tract and overgrowth of oropharyngeal taxa. PNAS 115:36E8489–98
    [Google Scholar]
  136. 136.
    Vonaesch P, Araújo JR, Gody JC, Mbecko JR, Sanke H et al. 2022. Stunted children display ectopic small intestinal colonization by oral bacteria, which cause lipid malabsorption in experimental models. PNAS 119:41e2209589119
    [Google Scholar]
  137. 137.
    Wagner VE, Dey N, Guruge J, Hsiao A, Ahern PP et al. 2016. Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition. Sci. Transl. Med. 8:366366ra164
    [Google Scholar]
  138. 138.
    Watanabe K, Petri WA. 2016. Environmental enteropathy: elusive but significant subclinical abnormalities in developing countries. EBioMedicine 10:25–32
    [Google Scholar]
  139. 139.
    Wichmann A, Allahyar A, Greiner TU, Plovier H, Lundén G et al. 2013. Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 14:5582–90
    [Google Scholar]
  140. 140.
    Winkler ES, Thackray LB. 2019. A long-distance relationship: the commensal gut microbiota and systemic viruses. Curr. Opin. Virol. 37:44–51
    [Google Scholar]
  141. 141.
    World Health Organ 2021. Levels and trends in child malnutrition. UNICEF/WHO/World Bank Group joint child malnutrition estimates WHO Rep. Geneva:
  142. 142.
    Wu SE, Hashimoto-Hill S, Woo V, Eshleman EM, Whitt J et al. 2020. Microbiota-derived metabolite promotes HDAC3 activity in the gut. Nature 586:7827108–12
    [Google Scholar]
  143. 143.
    Yan J, Herzog JW, Tsang K, Brennan CA, Bower MA et al. 2016. Gut microbiota induce IGF-1 and promote bone formation and growth. PNAS 113:47E7554–63
    [Google Scholar]
  144. 144.
    Zambruni M, Ochoa TJ, Somasunderam A, Cabada MM, Morales ML et al. 2019. Stunting is preceded by intestinal mucosal damage and microbiome changes and is associated with systemic inflammation in a cohort of Peruvian infants. Am. J. Trop. Med. Hyg. 101:51009–17
    [Google Scholar]
  145. 145.
    Zhao Y, Xiao X, Frank SJ, Lin HY, Xia Y 2014. Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β. Am. J. Physiol. Endocrinol. Metab. 307:2E186–98
    [Google Scholar]
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